The implantation of heart valve replacements is an increasingly frequent medical procedure. One of the principal topics of cardiac surgery and cardiology is the construction of heart valve replacements for clinical use.
Presently, whole porcine valves are commonly used as heart valve replacements in humans or the cusps of heart valve replacements are constructed from bovine pericardium. The disadvantage of such heart valve replacements is that they are xenogeneic to the immune system of the human patient and thus immunogenic. The patient's immune system reacts to such heart valve replacements and induces the development of degenerative changes in the heart valve replacement necessitating re-operation for heart valve replacement failure. To avoid infection of xenogeneic heart valve replacements and the development of degenerative changes, xenogeneic heart valves are subjected to strict sterilization procedures using crosslinking agents and other chemical treatments, such as stabilization in glutaraldehyde. As a result, the tissue of such a heart valve replacement is nonliving when implanted into the heart of the patient. Such tissue is inert to the biological environment and does not allow the infiltration and colonization of host cells that are necessary for the remodeling and maintenance of normal living heart valve tissue. This leads to the accumulation of degenerative changes and eventual failure of the heart valve replacement. There is also the potential for glutaraldehyde and other chemical agents to leach from the xenogeneic crosslinked heart valve replacements with the risk of cytotoxic effects in the patient.
Artificially created extracellular matrices seeded with living autologous cells represent another alternative method of constructing a heart valve replacement using tissue engineering. For example, U.S. Pat. No. 5,899,937 describes the decellularization and subsequent colonization of the extracellular matrix (ECM) of a porcine aortic heart valve using autologous cells harvested from the patient's skin. The disadvantage of this approach is that a nonliving xenogeneic matrix is used which is immunogenic to the patient. DE 100 53 014 and WO 96/39814 describe the use of tissue engineering methods for the seeding of artificial extracellular matrices with autologous cells and the placement of such seeded matrices in a pulsatile bioreactor containing culture medium to induce the proliferation of the colonizing cells upon the extracellular matrix. The disadvantage of this approach is the fact that the tissue created by this method is artificial and less durable than autologous human tissue as a consequence of poor cellular attachment and recognition of the foreign extracellular matrix by the colonizing cells.
Document U.S. Pat. No. 5,554,184 describes the application of autologous pericardium for the construction of a heart valve replacement. The disadvantage of the disclosed method is that the pericardium is stabilized and crosslinked in a solution of glutaraldehyde which kills the cells in the tissue. A heart valve replacement constructed by this method is not viable and is subject to the same problems as the aforementioned whole porcine and bovine pericardial heart valves, with the exception of immunogenic reaction to the extracellular matrix. Documents UA 77043, UA 67333, UA 63819 and UA 63826 describe the application of autologous pericardium for the construction of a heart valve replacement, for valvuloplasty of heart valve cusps, or for the repair of heart chamber defects (UA 63826). However, the harvested autologous pericardium is also treated in glutaraldehyde which means that dead tissue is used for the implantation.
The disadvantages of the above mentioned heart valve replacements also lies in their higher stiffness inducing higher flow gradients across the valve and inferior mechanical properties (the heart valve replacements being less pliable). Heart valves constructed from dead tissue are subject to dystrophic calcification resulting in failure of function of the heart valve replacement. The lifespan of such biological replacements is 10 to 15 years after which time it is necessary to remove the heart valve replacement and substitute it with a new one. Presently used mechanical heart valve replacements require long-term anticoagulation therapy because they are thrombogenic and increase the risk of infective endocarditis which reduces the quality of life of the patient.
The objective of this invention is to create a pericardial heart valve replacement that will remain functional for the course of the patient's lifetime, a replacement that possesses the same hemodynamic, mechanical and histological properties as the native human heart valve, that will be capable of ECM production, repair, remodeling and cellular homeostasis, and which is constructed from the patient's native tissue.